12-92777644-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003566.4(EEA1):​c.3913G>A​(p.Glu1305Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,648 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

EEA1
NM_003566.4 missense

Scores

4
8
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.88
Variant links:
Genes affected
EEA1 (HGNC:3185): (early endosome antigen 1) Enables 1-phosphatidylinositol binding activity; GTP-dependent protein binding activity; and protein homodimerization activity. Involved in endocytosis; vesicle fusion; and viral RNA genome replication. Located in cytosol and early endosome. Is extrinsic component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EEA1NM_003566.4 linkc.3913G>A p.Glu1305Lys missense_variant Exon 27 of 29 ENST00000322349.13 NP_003557.3 Q15075
EEA1XM_011538814.3 linkc.4039G>A p.Glu1347Lys missense_variant Exon 28 of 30 XP_011537116.1
LOC124902984XR_007063407.1 linkn.45C>T non_coding_transcript_exon_variant Exon 1 of 2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EEA1ENST00000322349.13 linkc.3913G>A p.Glu1305Lys missense_variant Exon 27 of 29 1 NM_003566.4 ENSP00000317955.8 Q15075

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1459648
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
726106
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 08, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3913G>A (p.E1305K) alteration is located in exon 27 (coding exon 27) of the EEA1 gene. This alteration results from a G to A substitution at nucleotide position 3913, causing the glutamic acid (E) at amino acid position 1305 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.27
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.24
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Benign
0.37
T
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.61
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D
M_CAP
Benign
0.050
D
MetaRNN
Uncertain
0.73
D
MetaSVM
Benign
-0.66
T
MutationAssessor
Benign
1.0
L
PrimateAI
Pathogenic
0.82
D
PROVEAN
Benign
-2.3
N
REVEL
Uncertain
0.44
Sift
Uncertain
0.0080
D
Sift4G
Uncertain
0.018
D
Polyphen
0.98
D
Vest4
0.65
MutPred
0.42
Gain of MoRF binding (P = 0.0033);
MVP
0.86
MPC
0.28
ClinPred
0.94
D
GERP RS
5.5
Varity_R
0.33
gMVP
0.67

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1873714735; hg19: chr12-93171420; API